While the management of substance abuse has been largely dependent on behavior modification, recent advances in neurochemistry have resulted in a growing realization that a rational pharmacotherapy founded on the neurochemistry of substance dependence may yield significant dividends. Drugs which are characterized by a high abuse liability belong to several structural and pharmacological classes (reviewed in G. DiChiara et al., PNAS, 85, 5274 (1988)). Pharmacological classes include central stimulants, central depressants, hallucinogens and narcotic analgesics. Although a similar degree of diversity characterizes the primary sites of action of these agents, recent evidence points to a common underlying mechanism for chemical dependence. For example, the rewarding effects of drugs such as morphine and cocaine have been associated with the preferential activation of the mesolimbic dopaminergic system (for review, see G. F. Koob et al., The Neuropharmacological Basis of Reward, Clarendon (1989) at pages 214-263).
On the basis of these observations, it has been suggested that drugs which antagonize the activation of these pathways may be potentially useful in the treatment of chemical dependence. Recent attempts to develop pharmacotherapy for cocaine abuse have focused on the neurochemistry of reward and withdrawal. Although cocaine primarily increases synaptic levels of monoamines, including dopamine, norepinephrine and serotonin, it is believed that repeated exposure to cocaine results in depletion of dopamine (for review, see W. L. Woolverton et al., Trends Pharmacol. Sci., 13, 193 (1992)). Consequently, drug-seeking behavior in the addict is presumed to be motivated by a) the desire to alleviate the unpleasant effects of withdrawal (attributed to dopamine depletion) and b) the desire to experience the pleasurable effects associated with cocaine self-administration.
Consistent with this view, dopamine agonists and antagonists have been proposed for treatment of withdrawal and for antagonizing the positive re-enforcing effects of cocaine. Although this approach presents some intriguing possibilities for the treatment of drug abuse, few clear successes have been reported. While the dopamine hypothesis of drug addiction continues to present a number of intriguing possibilities for the development of a useful pharmacotherapy of cocaine and opiate addiction, it is clear from these preliminary investigations that direct blockade of dopamine receptors may not be the most suitable pharmacological approach. Given the multiplicity of dopamine receptor subtypes and the absence of corresponding selective ligands, the final judgment on the viability of this approach may be not reached for a long time. In the interim, the need to pursue alternative leads remains unabated.
lbogaine is the major constituent of the root of Tabernanthe iboga, a naturally occurring shrub commonly found in West and Central Africa. The structure is shown in FIG. 1(A). Pharmacological evaluation of this agent in dogs and rabbits revealed unusual excitatory effects and local anesthetic activity. In a later evaluation of ibogaine as a potential phrenotropic agent, J. A. Schneider et al., Ann. NY Acad. Sci., 66, 765 (1957) confirmed that ibogaine was a psychostimulant which caused phobia, ataxia and tremors in cats.
The anti-addictive effects of ibogaine were first reported by drug addicts seeking new psychoactive agents. Administration of ibogaine was followed by a period of hallucinations (lasting several hours), followed by a longer cognitive phase of intense introspection. At the end of this period, some addicts reported alleviation or cessation of craving, and a few remained drug-free for several years thereafter. Although these earlier reports were anecdotal, a method for the treatment of cocaine and opiate abuse based on ibogaine was subsequently patented by Lotsoff in 1985 (U.S. Pat. No. 4,499,096). Subsequent investigation of ibogaine in rodents and monkeys has prompted the initiation of limited human trials. A marked reduction in cocaine self-administration is evident in some animals after a single dose of this compound. However, other animals required up to three doses to exhibit comparable effects (S. D. Glick et al., Brain Res., 628, 201 (1994)). Similarly, ibogaine was effective in reducing craving in some humans while others were unaffected.
Despite the positive results in animals, the clinical utility of ibogaine may be severely limited. Ibogaine apparently interacts with a diverse number of molecular targets (J. C. Deecher et al., Brain Res., 571,242 (1992)). This multiplicity of active sites is manifested in vivo in a number of undesirable side-effects. Specifically, ibogaine (and related compounds) are hallucinogenic (J. A. Schneider et al., Ann. NY Acad. Sci:, 66, 765 (1957)), tremorigenic (G. Zetler et al., Pharmacology, 7, 237 (1972); G. Singbartl et al., Neuropharmacol., 12, 239 (1973)) and, at higher doses, excitotoxic (E. O'Hearn et al., NeuroReport, 4, 299 (1993), E. O'Heam et al., Neurosci., 55, 303 (1993)).
Ibogaine analogs formally based on fragmentation of the parent compound have also been prepared and, in some cases, investigated for bioactivity. S. D. Glick et al., Brain Res., 628, 201 (1993) (FIG. 1(C)) recently reported that the ibogaine analogs R-ibogaine (FIG. 1(B)) and R-coronaridine (FIG. 1(C)) reduced dopamine levels in the nucleus accumbens and striatum.
The substructure 1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (FIG. 1(D)) and some of its derivatives were synthesized years ago as a means of restraining the conformational mobility of the aminoethyl fragment of tryptamine (J. B. Hester et al., J. Med. Chem., 11, 101 (1968)). One of these compounds, 6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole was found by Hester et al. to antagonize aggressive behavior in fighting mice, block conditioned avoidance, and induce hypothermia and anorexigenic behavior in rodents. However, the compound did not exhibit neuroleptic activity in humans (D. M. Gallant et al., Current Therapeutic Res., 9, 579 (1967)). In a subsequent report, A. J. Elliott et al., J. Med. Chem., 23, 1268 (1980) described a series of 5-phenyl-1,2,3,4,5,6-hexahydroazepino[4,5b]indoles. In mice, these compounds failed to exhibit neuroleptic activity. However, two analogues, 5-phenyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole and 3-methyl-5-phenyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole, displayed antidepressant activity. The antidepressant properties of these analogues are reminiscent of ibogaine. The synthesis of 2-alkyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indoles has been reported in the patent literature (Gadient, EPA, 28,381 (1981)). However, no biological data were provided.
Therefore, a need exists for the preparation and characterization of bioactive ibogaine analogs, particularly those useful to treat substance abuse, i.e., cocaine or opiate addiction.